PROJECT SUMMARY/ABSTRACT Millions of workers in the U.S. are exposed to suspected nephrotoxins and carcinogens, yet epidemiologic studies of occupational kidney disease and kidney cancer are challenged by low power and poor exposure assessment. Metalworking fluids (MWFs), which are used to lubricate and cool metal during cutting and grinding processes, are among the widely used industrial exposures which may have adverse consequences for the kidney. MWFs consisting of straight mineral oils (also called straight MWFs) are a source of polycyclic aromatic hydrocarbons (PAHs). PAHs in general and MWFs in particular have been associated with other cancers, but inconsistent results have been reported for kidney disease and kidney cancer in occupational settings. The General Motors-United Autoworker (GM-UAW) cohort study provides an opportunity to overcome the main barriers of previous occupational studies in examining the association between MWFs and kidney outcomes due to its large size (over 46,000 subjects), over 60 years of follow-up, and quantitative exposure estimates of different types of MWFs, including straight MWFs. Further, we have available records of other potentially harmful occupational exposures in the GM-UAW plants which may be confounders. Therefore, to investigate the association between MWFs, kidney cancer, and end-stage renal disease (ESRD), the preferred outcome of PAH-induced kidney disease, we will: 1) conduct an industrial hygiene review to characterize any other occupational exposures (other than MWFs) in the GM- UAW cohort in order to better control for confounding; 2) determine the relationship between straight MWFs and kidney cancer incidence; and 3) estimate the dose-response relationship between straight MWFs and ESRD. We will also analyze subtypes of kidney cancer and ESRD, which may be important in reducing disease misclassification and providing better estimates of the associations with MWFs. As with any occupational study, these relationships in the GM- UAW cohort may be underestimated due to healthy worker survivor effect (HWSE) (i.e., when workers in poor health remove themselves from exposure) and left truncation (i.e., when subjects are hired prior to the start of follow-up). In order to remove these biases, we will employ preferred modeling strategies including g-estimation and accelerated failure time models. By evaluating multiple kidney endpoints, we will be able to examine the overall impact of MWFs on the kidney, as these outcomes are interrelated. This research will advance our knowledge of the burden of kidney disease due to occupational exposures and can help direct preventive measures to protect workers.